Interleukin-12 (IL-12) is a hetero-dimeric inflammatory cytokine (also called IL-12p70) comprising two subunits named p35 and p40 respectively and plays an important role in the immune response through a mediatory action between the innate resistance and the antigen-specific adaptive immunity. In addition, IL-12 is produced by the phagocyte and the antigen-presenting cells, in particular, macrophages and the dendritic cells through the stimulative actions of, for instance, bacteria, bacterial products such as lipopolysaccharides (LPS) and intracellular parasites. A well-known biological function of IL-12 is to express interferon-γ (IFN-γ) through T cells and NK cells and to induce the differentiation thereof into a Th1 T lymphocyte type one. On the other hand, interleukin-23 (IL-23) is, like IL-12, a hetero-dimeric inflammatory cytokine comprising two subunits named p19 and p40 respectively and it is involved in the type I immunological protection and induces the secretion of IFN-γ through T cells.
As has been discussed above, IL-12 and IL-23 possess p40 common thereto and play an important role in the immunological inflammatory reactions, while it has been suggested that the production of IL-12 is enhanced by IFN-γ in the chronic diseases accompanied by the continuous production of IFN-γ. Accordingly, it has been recognized that the quite strong feedback loop appearing subsequent to the infectious stimulation or inflammatory stimulation which would induce the production of IL-12 may accelerate the further production of IL-12 by the action of the IL-12 inducible and IL-23 inducible IFN-γ and thus results in the excess production (hyperproduction) of inflammation-accelerative cytokines.
It have been known that the excess production of IL-12/IL-23 takes part in a variety of diseases and, more specifically, it would be involved in various diseases, examples of which include, but are not limited to, multiple sclerosis, systemic sclerosis, sepsis, myasthenia gravis, autoimmune neurosis, Guillain-Barre syndrome, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti-phospholipid syndrome, vasculitis, Wegener granulomatosis, Behcet disease, psoriasis, psoriatic arthritis, herpetic dermatitis, pemphigus vulgaris, leukoma, Crohn's disease, ulcerative colitis, interstitial pulmonary fibrosis, myelofibrosis, hepatic fibrosis, myocarditis, autoimmune thyroiditis (such as Grebs' disease and Hashimoto's disease), primary biliary cirrhosis, autoimmune hepatitis, immune-mediated diabetes mellitus, autoimmune ovaritis and orchitis, autoimmune adrenalitis, articular rheumatism, juvenile articular rheumatism, systemic lupus erythematosus, scleroderma, multiple myositis, dermatomyositis, spondyloarthropathy, rigid spondylitis, Sjogren's syndrome, and graft-versus-host disease.
On the other hand, TNF-α is, like IL-12/IL-23, one of the inflammatory cytokines which play a central role in, for instance, the pathema-formation of articular rheumatism. In fact, there have been used, even in the clinical practice in Japan, a biological preparation which acts on TNF-α as a target and there have been adapted, for instance, etanercept which is a fused protein comprising sTNFR and immunoglobulin G and infliximab and adalimumab which are anti-TNF-α monoclonal antibodies. However, TNF-α is considered to be a cytokine which is quite important in the immune response and positioned upstream of the immune response signal and all of the aforementioned drugs in fact suffer from various side effects and accordingly, there would be apprehension that the use thereof may accompanied with much risks of causing infectious diseases and of producing cancers.
For this reason, the compounds each capable of inhibiting the production of IL-12/IL-23 show a high selectivity for IL-12/IL-23-excess production-related diseases, are free of any harmful side effect and can serve as clinically quite useful agents for preventing and treating a variety of inflammatory diseases inclusive of the aforementioned respective diseases.
Patent Documents 1 to 9 each disclose a compound possessing the IL-12 excess production-inhibitory action, but the compounds disclosed therein each have a skeleton different from the pyrazolo[1,5-a]pyrimidine skeleton according to the present invention.
Patent Documents 10 and 11 each disclose a condensed heterocyclic compound having a MAPKAP kinase-2 (MK2)-inhibitory action, but these documents never state that these compounds possess any IL-12/IL-23 production-inhibitory action like that of the compound according to the present invention. Patent Document 12 discloses condensed heterocyclic compounds each showing a cJun N-terminal kinase (JNK)-inhibitory action, but this document never states that these compounds show any IL-12/IL-23 production-inhibitory action like that of the compound according to the present invention. Patent Document 13 discloses a bicyclic heterocyclic compound useful for the immunological enhancement, but this document never states that these compounds show any IL-12/IL-23 production-inhibitory action like that of the compound according to the present invention. Cited Reference 14 discloses bicyclic heterocyclic compounds each possessing an agonist activity against adenosine receptor A2, but this document never states that these compounds show any IL-12/IL-23 production-inhibitory action like that of the compound according to the present invention. Cited Reference 15 discloses bicyclic heterocyclic compounds each possessing an antagonistic action against corticotrophin-release factor, but this document never states that these compounds show any IL-12/IL-23 production-inhibitory action like that of the compound according to the present invention.
Accordingly, there has been desired for the development of a clinically quite useful agent for preventing or treating a variety of inflammatory diseases including those specified above, shows an IL-12/IL-23 production-inhibitory action, has a high selectivity for IL-12/IL-23-excess production-related diseases, and are free of any harmful side effect.